| Topic | Key findings | Key quantitative/statistical values (if any) | Best supporting citations |
|---|---|---|---|
| Definition/function | Hsp104 in *Saccharomyces cerevisiae* is a hexameric AAA+ ATP-dependent disaggregase of the Hsp100/ClpB family that rescues proteins trapped in aggregated states and is central to acquired thermotolerance. Foundational work showed that Hsp104 expression is sufficient for thermotolerance and that Hsp104 promotes resolubilization/reactivation of heat-damaged proteins. | Thermotolerance sufficiency demonstrated by induced Hsp104 expression; no single numeric enzyme constant reported in the available excerpts. | (pqac-00000013, pqac-00000015) |
| Mechanism/domains | Each protomer contains NBD1 and NBD2 separated by a regulatory middle domain (MD), plus N- and C-terminal regions. Hsp104 uses pore-loop-mediated substrate gripping and ATP-driven threading/translocation through a central channel; structural work supports an unfolding/threading or ratchet-like mechanism, with nucleotide-state-specific MD:NBD contacts tuning activity. | Hsp104R419E ATPase activity is reported at ~70% of WT in one 2024 engineering study. | (pqac-00000012, pqac-00000001, pqac-00000005, pqac-00000018) |
| Partners/pathway | Hsp104 works in a multichaperone disaggregation pathway with Hsp70 and Hsp40; Hsp40 promotes Hsp70 engagement, and Hsp70/Hsp40 help recruit/activate Hsp104 on aggregates. Hsp110/Sse1-Sse2 further powers the pathway by regenerating Hsp70-ATP and is required for efficient Hsp104-dependent disaggregation in cytosol and nucleus. | In Hsp110-defective cells, Hsp70 recruitment to aggregates can be delayed to >120 min, and aggregate metrics remain largely unchanged over a 120-min recovery window. | (pqac-00000010, pqac-00000032, pqac-00000003) |
| Localization | Hsp104 is largely cytosolic under non-stress conditions but relocalizes to stress-induced foci associated with CytoQ/Q-bodies, stress granules, and nuclear quality-control deposits such as INQ/IPOD. It is recruited to aggregate foci in both cytosol and nucleus and can also be engineered to drive aggregate relocalization to buds or organelle-associated inclusions. | During metabolic stress, Hsp104-marked compartments dissolve within minutes after glucose/ATP restoration; Hsp104 recruitment after heat shock is seen immediately, including in cells with compromised Hsp110 function. | (pqac-00000024, pqac-00000025, pqac-00000030) |
| Prion biology | Hsp104 is essential for propagation of amyloid yeast prions such as [PSI+] because it fragments fibrils into transmissible seeds/propagons. Hsp104 levels must be finely balanced: deletion or inhibition eliminates prions, while overexpression can cure [PSI+], and Hsp70/Ssa1 can antagonize this curing activity. | Both deletion and overexpression cure [PSI+]; no exact percentage reported in the available excerpts, but the effect is genetically robust. | (pqac-00000014, pqac-00000036, pqac-00000037, pqac-00000011) |
| Recent developments (2023–2024) | Recent work refined Hsp104 regulation by showing that ATP- versus ADP-state MD:NBD contact networks tune Hsp70 collaboration and toxicity, and that the MD helps ensure substrates remain functional after processing. Additional 2024 prion work linked exposed Hsp70-binding sites on Sup35 amyloid to efficiency of the Hsp70-Hsp104 disaggregation cascade. | Plasmid-driven expression in one 2024 study yielded ~4-fold over endogenous Hsp104 steady-state levels. | (pqac-00000005, pqac-00000000, pqac-00000002) |
| Applications | Hsp104 is being repurposed in proteostasis engineering: engineered variants can be made substrate-selective, including variants that selectively detoxify α-synuclein, and synthetic Hsp104-based systems can forcibly relocalize aggregates in yeast and even influence aggregate behavior in human cells. These applications make Hsp104 a leading model for therapeutic disaggregase design and synthetic cell biology. | α-synuclein-specific engineered variants reduced dopaminergic neurodegeneration in a *C. elegans* Parkinson model; qualitative protection from mother-cell death was shown when mutant huntingtin inclusions were removed from mothers. | (pqac-00000034, pqac-00000021, pqac-00000033) |
| Quantitative data | Available studies provide useful in vivo and mechanistic metrics for Hsp104-dependent proteostasis. Under glucose starvation, Hsp104-GFP foci become common and enlarge substantially as ATP falls, and stress-granule/Q-body dissolution is rapid upon ATP restoration. | 0.2% glucose for 90 min: cells with one Hsp104-tagged aggregate increase from ~4% to ~40%, with ~25% showing ≥2 foci; median aggregate size ~800 nm. 0.02% glucose: ~40% of cells have one aggregate and ~50% have ≥2; median size ~1200 nm, with ~12% >1500 nm. ATP falls >2-fold in 30 min and ~5-fold by 90 min in 0.2% glucose, or ~10-fold within 1 h in 0.02% glucose. Stress-granule foci begin resolving within ~2 h of recovery from heat shock in WT cells. | (pqac-00000038, pqac-00000024, pqac-00000028) |


*Table: This table summarizes the main evidence for the identity, mechanism, pathway context, localization, prion roles, recent advances, applications, and quantitative findings for yeast Hsp104. It is useful as a compact citation-backed map of the strongest claims to include in a full research report.*